P1097: CD20 CAR-T THERAPY WITH MB-106 FOR BTK INHIBITOR-REFRACTORY WALDENSTRÖM MACROGLOBULINEMIA (WM)/ LYMPHOPLASMACYTIC LYMPHOMA (LPL) – SINGLE INSTITUTION STUDY
Authors: Mazyar Shadman, Cecilia Yeung, Mary W Redman, Sang Yun Lee, Dong Hoon Lee, Susan Ra, David H Qian, Bruce Dezube, Aude Chapuis, Damian Green, Andrew Cowan, Ryan Cassaday, Hans-Peter Kiem, Houston E Warren, Filippo Milano, Jordan Gauthier, Alexandre Hirayama, Mary Kwok, Chaitra Ujjani, David Maloney, Ajay Gopal, Brian Till
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Chimeric antigen receptor T-cell (CAR-T) therapy is the standard of care for various B non-Hodgkin lymphoma (B-NHL) histologies, but it is currently not approved for Waldenström macroglobulinemia (WM)/ lymphoplasmacytic lymphoma (LPL). There is also very limited experience with investigational CAR-Ts for WM/LPL with one published report on 3 patients (pts); each received a different anti-CD19 CAR-T (Palomba et al., J Immunother Cancer, 2022). MB-106 is a third generation fully human CD20 targeting CAR-T with high activity and favorable safety profile in follicular lymphoma (FL) and other B-NHLs (Shadman et al., EHA, 2022). We report the preliminary results of the WM/LPL cohort of our ongoing phase I/II clinical trial investigating MB-106 for B-NHL. Aims: To assess safety and efficacy of CD20 CAR-T for treatment of relapsed WM Methods: In this single-institution study conducted at the Fred Hutchinson Cancer Center, pts with relapsed/refractory B-NHLs including WM/LPL were eligible after confirmation of CD20 expression. Lymphodepletion (LD) consists of cyclophosphamide + fludarabine. CAR-T cells are administered at one of 4 dose levels (DL): DL1: 3.3x105, DL2: 1x106, DL3: 3.3x106, DL4: 1x107 CAR T cells/kg. A continual reassessment method dose escalation design was used to find the maximally tolerated dose. CAR-T was infused in the outpatient setting except for the first pt of each dose cohort (overnight observation). Initial treatment response is assessed on day 28 and best response by IWWM-7 is reported here. CRS and ICANS are graded per ASTCT. Results: Between 7/2021-2/2023, 6 patients with WM received MB-106, and 4 had response assessment at the data cut-off. Three of 4 were male with a median age of 67.5 (range 51-71). Median time from diagnosis was 9.5 yrs (range 5-29), and median prior treatment lines was 6.5 (range 2-12). All pts had a mutated MYD88L265P, and 2 of 2 tested pts had wild type CXCR4. All 4 pts had BTKi refractory disease (2 ibrutinib, 1 acalabrutinib, 1 zanubrutinib). Before CAR-T therapy, risk categories included: 1 high-risk, 2 intermediate risk and 1 low-risk. Median B2M pre-CAR-T was 4.4 mg/dL (range 1.6-10.8), and 2 pts had extramedullary disease with PET-avid lymphadenopathy, and 3 of 4 had anemia (<11 g/dL) at baseline. Median pre-CAR-T IgM was 2873 mg/dL (range 547-5492; ULN 350). By flow cytometry, median marrow involvement by abnormal B-cells was 24% (range 1.4-25%). One pt received bridging therapy with bendamustine after leukapheresis and before CAR-T infusion (3 DL3 and 1 DL2). All 4 pts developed CRS (2 grade 1, 2 grade 2); no pts had grade 3 or 4 CRS. One pt had grade 1 ICANS. One pt developed pneumonia before day 28. On day 28, no patient had grade 3 or 4 anemia, neutropenia or thrombocytopenia. There no evidence of IgM flare By IWWM-7, all patients responded to treatment (2CR, 1 PR and 1 MR). Both pts with PET-avid disease at baseline achieved a complete metabolic response by PET. There were no remaining detectable abnormal B-cells in the marrow of all 4 pts. One pt died from complications of COVID-19 while in a CR 7 months after treatment. The other 3 pts are free of progression at 1.5+, 3+ and 19+ months. Summary/Conclusion: Early results of CD20 CAR-T therapy with MB-106 for BTKi-refractory WM/LPL suggest high efficacy and favorable safety profile with no grade 3/4 CRS and no grade 2/3/4 ICANS. MB-106 has received orphan drug designation by the US FDA for WM, and a multicenter study is currently active in the US for WM and other B-NHLs. Enrollment also continues in this single institution study, and the results will be updated during the presentation. Keywords: CAR-T, Waldenstrom's macroglobulinemia